CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts

Laura Curti, Sara Rohban, Nicola Bianchi, Ottavio Croci, Adrian Andronache, Sara Barozzi, Michela Mattioli, Fernanda Ricci, Elena Pastori, Silvia Sberna, Simone Bellotti, Anna Accialini, Roberto Ballarino, Nicola Crosetto, Mark Wade, Dario Parazzoli and Stefano Campaner ()
Additional contact information
Laura Curti: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Sara Rohban: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Nicola Bianchi: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Ottavio Croci: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Adrian Andronache: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Sara Barozzi: The AIRC Institute of Molecular Oncology
Michela Mattioli: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Fernanda Ricci: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Elena Pastori: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Silvia Sberna: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Simone Bellotti: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Anna Accialini: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Roberto Ballarino: Tumor and Cell Biology, Karolinska Institutet
Nicola Crosetto: Tumor and Cell Biology, Karolinska Institutet
Mark Wade: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)
Dario Parazzoli: The AIRC Institute of Molecular Oncology
Stefano Campaner: CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The identification of genes involved in replicative stress is key to understanding cancer evolution and to identify therapeutic targets. Here, we show that CDK12 prevents transcription-replication conflicts (TRCs) and the activation of cytotoxic replicative stress upon deregulation of the MYC oncogene. CDK12 was recruited at damaged genes by PARP-dependent DDR-signaling and elongation-competent RNAPII, to repress transcription. Either loss or chemical inhibition of CDK12 led to DDR-resistant transcription of damaged genes. Loss of CDK12 exacerbated TRCs in MYC-overexpressing cells and led to the accumulation of double-strand DNA breaks, occurring between co-directional early-replicating regions and transcribed genes. Overall, our data demonstrate that CDK12 protects genome integrity by repressing transcription of damaged genes, which is required for proper resolution of DSBs at oncogene-induced TRCs. This provides a rationale that explains both how CDK12 deficiency can promote tandem duplications of early-replicated regions during tumor evolution, and how CDK12 targeting can exacerbate replicative-stress in tumors.

Date: 2024
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DOI: 10.1038/s41467-024-51229-5

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